Reduced‐dose chemotherapy followed by blinatumomab in induction therapy for newly diagnosed B‐cell acute lymphoblastic leukemia

Abstract Background Blinatumomab early‐line treatment in B‐cell precursor acute lymphoblastic leukemia (B‐ALL) might improve clinical outcomes. Methods We conducted a retrospective real‐world cohort analysis in 20 newly diagnosed B‐ALL patients who received reduced‐dose chemotherapy (idarubicin, vindesine, and dexamethasone) for 1–3 weeks, followed by blinatumomab for 1–4 weeks as an induction therapy. Results At the end of the induction therapy, a complete remission rate of 100% was achieved; 17 (85%) patients were minimal residual disease (MRD) negative (<1 × 10−4). Adverse events (AEs) were reported in 12 (60%) patients—43.8% were grade 1–2 and 56.2% were grade 3–4. No incidence of neurotoxicity or grade ≥3 cytokine release syndrome was reported. Conclusions Blinatumomab demonstrated a significant improvement in clinical outcomes in patients with newly diagnosed B‐ALL irrespective of their poor‐risk factor status and the pretreatment blast burden.


| INTRODUCTION
For nearly 30 years, induction regimens for adult patients with B-cell acute lymphoblastic leukemia (B-ALL) have mainly been modified based on pediatric multidrug combination chemotherapy regimens. 1The hyper-fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (Hyper-CVAD) and pediatric Augmented Berlin-Frankfurt-Münster (ABFM) are two established treatment regimens with convincing favorable outcomes in B-ALL, 2 though Hyper-CVAD is associated with a better safety profile compared to ABFM. 3 However, the depth of remission with currently available regimens is so limited that half of the adult patients with B-ALL relapse leading to poor survival outcomes. 4,5Therefore, balancing the efficacy and safety of treatment for adult B-ALL patients remains a major challenge.The advent of targeted and immunotherapies has changed the landscape of B-ALL treatment.The use of tyrosine kinase inhibitor (TKI) in Philadelphia chromosome-positive B-ALL (Ph + B-ALL) induction therapy has substantially reduced the intensity of chemotherapy and related mortality while increasing the remission rate and thereby improving the prognosis. 6ith the addition of immunotherapeutic agents such as blinatumomab, a bispecific anti-CD3 and anti-CD19 monoclonal antibody, patients with relapsed or refractory as well as minimal residual disease (MRD)-positive B-ALL have also achieved a higher molecular response and longer survival. 7,8The approval of blinatumomab is   an important milestone especially for the treatment of relapsed or refractory Philadelphia chromosome-negative B-ALL (Ph − B-ALL), a subtype that lacks the molecular targets for targeted therapies. 9,10Encouraging clinical efficacy data have also been observed for blinatumomab in the early-line setting as sequential therapy in B-ALL. 11In current study, we evaluated the efficacy and safety profile of blinatumomab in induction therapy of newly diagnosed patients with B-ALL.

| METHODS
This retrospective study consecutively included newly diagnosed patients with B-ALL who had received blinatumomab as the initial induction therapy at four hematology treatment centers in Jiangsu Province in China between December 2021 and October 2022.Before blinatumomab, all patients were treated with a small amount of chemotherapy or corticosteroid, and we defined this pretreatment as reduced-dose chemotherapy (RDC).The RDC treatment period spanned for 1-3 weeks and contained idarubicin (IDA), vindesine (VDS), and dexamethasone (DEX), which were administered at a dose of 8 mg/m 2 for IDA (median dose: 0; range, 0-3), 3 mg/m 2 for VDS (median dose: 1; range, 0-3), and 9 mg/m 2 /day for DEX (median duration: 7 days; range, 0-21).Blinatumomab was given at a dose of 9 μg/day for the first 7 days and 28 μg/day for the remaining days (median duration: 28 days; range, 7-28).This study was approved by institute's ethics committee and was conducted in accordance with Declaration of Helsinki.Efficacy outcomes included complete remission (CR) and MRD negativity.Safety data including cytokine release syndrome (CRS) and neurological symptoms were collected.Most bone marrow evaluations were performed after 2 weeks of blinatumomab treatment, and response criteria for blood and bone marrow were defined according to the National Comprehensive Cancer Network Guidelines (Version 1.2022).MRD was assessed by multicolor flow cytometry, and the threshold of MRD was 1 × 10 −4 .Neutrophil and platelet deficiencies were defined as count <0.5 × 10 9 /L and < 20 × 10 9 /L, respectively.The grading of adverse events (AEs) was based on the Common Terminology Criteria for Adverse Events Version 5.0.CRS and neurotoxicity were evaluated according to the American Society for Transplantation and Cellular Therapy Consensus Grading. 12

| RESULTS
Overall, 20 patients were enrolled; Ph − B-ALL was the most common subtype diagnosed in 11 (55%) patients.The median age of the cohort was 44 years (range, 8-92; Supplementary Table S1).Twelve (60%) patients were identified with a risk factor; BCR::ABL1 was the most common risk factor found in six (50%) patients (Table 1).All patients received RDC followed by blinatumomab as induction regimen.The reasons for patients not completing the conventional first-line chemotherapy included chemotherapy-related toxicities (4/20; sepsis [n = 1], infectious shock [n = 1] and pneumonia [n = 2]), chemotherapy insensitivity (3/20), severe comorbidity or underlying disease at initial diagnosis (10/20), and patient-requested chemo-free therapy (3/20; Table 1).For patients with Ph + B-ALL (n = 6), TKI was continuously used after the detection of Philadelphia chromosome.Three patients with mixed-phenotype acute leukemia (MPAL) had 10-19 days of venetoclax added to their induction therapy (Table 1).Some patients had an interval before or after the RDC treatment due to an infection or waiting for the results of bone marrow evaluation (Figure 1).
Nine (45%) patients underwent bone marrow evaluation before treatment with blinatumomab, and none of the RDC treatments resulted in CR.Nevertheless, at the end of the induction therapy, all 20 (100%) patients achieved CR after a median duration of 25 days (range, 19-56), and 17 (85%) patients achieved MRD negativity (Supplementary Table S1).A 92-year-old patient (who discontinued blinatumomab after 7 days due to fatigue) and  2 patients with MPAL (their lowest MRD was 2.6 × 10 −4 and 2.5 × 10 −3 , respectively) did not achieve MRD negativity (Table 1).Further, of the 6 Ph + B-ALL patients with BCR::ABL1, 2 achieved complete molecular response (BCR::ABL1 negative by quantitative PCR) at the end of initial induction treatment and other 4 achieved it on subsequent treatments.
The median duration of blinatumomab infusion before achieving CR or MRD negativity was 14 days for both outcomes (range, 7-28 for CR and 12-28 for MRD negativity; Table 1).After the induction therapy, patients were treated with either multidrug combination chemotherapy (based on high-dose cytarabine or methotrexate) or blinatumomab (28 days per cycle) as consolidation regimens.The median cycles for consolidation therapy were 2 cycles (range, 1-7).By November 2022, only one patient had a bone marrow relapse at Day 254, and the median follow-up was 103 days (range, 31-334) with 100% overall survival.

| DISCUSSION
Given the success of blinatumomab in treating relapsed or refractory B-ALL, it has been proposed that the addition of blinatumomab to chemotherapy in the early-line setting may further improve long-term prognosis. 11However, the clinical outcomes of treatment in real-world may differ outside of the controlled settings of clinical trials. 13herefore, this real-world study was conducted to evaluate the efficacy and toxicity of blinatumomab in newly diagnosed patients with B-ALL and summarize the experience of using blinatumomab.
Overall, the efficacy of blinatumomab in the realworld setting was consistent with that reported in clinical trials.The results from our study were in line with a phase 2 trial that evaluated the use of hyper-CVAD in sequential combination with blinatumomab in newly diagnosed patients with B-ALL and reported a 100% CR and MRD negativity of 96%. 11Also, the induction regimen in our study demonstrated a comparable efficacy to mini-hyper-CVD + inotuzumab ozogamicin +/− blinatumomab regimen that resulted in overall response rate of 91% and MRD-negativity rate of 84% after 1 cycle of induction therapy in a phase 2 trial in newly diagnosed patients with B-ALL, but blinatumomab appeared to be better tolerated (inotuzumab ozogamicin related grade 3-4 liver toxicities were observed in 26.2% patients and veno-occlusive disease was observed in 8% patients). 14he use of RDC followed by blinatumomab as the induction therapy in our study was a better drug combination for newly diagnosed patients with B-ALL.With the early use of blinatumomab, patients with Ph + B-ALL could obtain CR and MRD negativity more rapidly, which showed an advantage compared with the phase 2 D-ALBA trial from the Italian GIMEMA Group (median duration of induction: 25 vs. 85 days). 9The clinical trial SWOG 1318, where blinatumomab was used as a single-agent induction therapy in newly diagnosed patients with Ph−B-ALL, 15 reported an overall response rate of only 66% that was far less effective than that of multidrug combination chemotherapy.Furthermore, in another clinical trial of chemotherapy combined with blinatumomab, ALL08, the chemotherapy dose was not substantially reduced, and hence, the incidence of chemotherapy-related AEs remained high. 16The trial ALL08 reported 53 episodes of sepsis, infection or febrile neutropenia and 1 grade 3 CRS versus 2 episodes of sepsis and infectious shock and no grade 3 CRS in our study.Moreover, no incidence of neurotoxicity was reported in our study compared with seven episodes in the ALL08 study 16 and one episode of neurological disorder in the D-ALBA study. 9The incidence of overall grade 3 events was also less in our study (8 events) compared with the D-ALBA study (21 events).Hence, our induction therapy study found a good balance between chemotherapy and immunotherapy, minimizing the chemotherapy-related complications and increasing the efficacy of induction therapy.After a median duration of 1 week of RDC followed by 14 days of blinatumomab, 100% CR rate was achieved along with an early MRD negativity in 85% of patients, which was very important to reduce the recurrence rate and prolong survival. 17,18otably, there were only three cases of MPAL, and our study was the first to use venetoclax in combination with blinatumomab as the induction therapy in such patients, which achieved a very good efficacy (100% CR).Moreover, despite 60% of patients presenting with one or the other poor-risk factors and a high blast burden of 82.9% at baseline in our study, 100% CR was achieved with blinatumomab.Therefore, blinatumomab was well tolerated and effective in the treatment of newly diagnosed patients with B-ALL, irrespective of their poorrisk factor status and high blast burden.
Our study was limited by its small sample size, singlearm design, and relatively short follow-up.Owing to these limitations, we are conducting a study (NCT05557110) in newly diagnosed nonelderly patients with Ph−B-ALL to further validate the efficacy of RDC followed by blinatumomab as the induction therapy.
To conclude, this is a retrospective real-world study that evaluated the efficacy and safety of blinatumomab in newly diagnosed B-ALL.This study supports the use of blinatumomab for the early treatment of B-ALL and summarized the dose balance between chemotherapy and blinatumomab, which could help improve survival outcomes and limit chemotherapy-related toxicity.

a
All the patients were diagnosed according to the 2016 WHO classification of Tumours of Haematopoietic and Lymphoid Tissues.bThe poor-risk factors of ALL were identified according to the NCCN guideline for ALL (Version 1, 2022), while the poor-risk factors of MPAL also refer to the NCCN guideline for AML (Version 1, 2022).cThe dosage of RDC during induction treatments is 8 mg/m 2 /dose for IDA, 3 mg/m 2 /dose for VDS, and 9 mg/m 2 /day for DEX.dThe dosage of Blina during induction treatments is 9 μg/day for the first 7 days and 28 μg/day for the rest days.

1
Process and response of induction therapy.
Baseline characteristics and induction therapy data at patient level.
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